Recent clinical studies suggest that hawthorn may be beneficial in the treatment of systolic heart failure. Basic studies, which have focused on acute effects of hawthorn on contractility and cardioprotection, have also suggested important benefits. These findings have brought hawthorn to the forefront of complementary alternative medicines for the treatment of heart failure. Clearly these limited findings need to be expanded if hawthorn or the constituents of hawthorn are to be embraced for the treatment of heart failure. One area where these findings need to be expanded is the mechanism(s) by which hawthorn may affect heart failure at a cellular level. This is the overall goal of this proposal; to determine how hawthorn, at a cellular and functional level, affects the development of systolic heart failure over time. It is hypothesized based in part on the number of compounds contained in a preparation of hawthorn that known protein and gene expression that are important in the development and maintenance of heart failure will be attenuated. To evaluate this concept this proposal is divided into three specific aims. The first specific aim (SA1) will determine the effect of hawthorn on myocardial function and corresponding contractile proteins including alpha- and beta-myosin heavy chains, sacroplasmic reticulum Ca-ATPase, and the genes that may regulate these proteins. The second specific aim (SA2) will evaluate the effect of hawthorn on the development of fibrosis. The third specific aim (SA3) will evaluate the effect of hawthorn on apoptosis. Overall these specific aims will determine the effect of hawthorn on myocardial function and known biochemical markers that are responsible for heart failure. In order to establish the mechanisms (SA1, SA2, SA3) by which hawthorn may be beneficial in heart failure an aortic constriction model in rats will be employed. This model is a practical model to work with since the development of heart failure is predictable and the hypertrophy response includes numerous phenotypic and genotypic features that are consistent with pathological cardiac hypertrophy and will address our specific aims. For this proposal hawthorn at three different dose levels will be administered at the time of surgically induced aortic constriction. Animals will be sacrificed at 5 weeks and at the time at which 50% of the placebo group develops symptomatic heart failure to address each specific aim. This study will determine how hawthorn, at a cellular and functional level, affects the development and maintenance of systolic heart failure. Completion of this study will clearly establish whether or not hawthorn has important mechanistical effects on the pathophysiology of heart failure and if so will make further studies of hawthorn in the treatment of heart failure a high priority. The results from this study will have important translation to both the basic and clinical research settings.